The compound umeclidinium bromide of molecular structure (I) depicted below is a long-acting muscarinic antagonist used in the treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

The synthesis of umeclidinium bromide has been claimed in WO2005/104745 involving four steps as follows:

The key intermediate ethyl 1-(2-chloroethyl)piperidine-4-carboxylate of formula (II) is synthesized by reacting 1-bromo-2-chloroethane and ethyl isonipecotate in the presence of potassium carbonate in acetone. However, the compound of formula (II) is prepared in very low yields (39%), due to the formation of a dimer by-product, diethyl 1,1′-(ethane-1,2-diyl) bis(piperidine-4-carboxylate) (V), which must be separated from the primary compound by chromatographic techniques.

In order to overcome the dimerization issue and consequent low yields, WO2014/027045 claims an alternative two-step process for the preparation of the compound of formula (II) in better yield (80%) as follows:

There is no doubt that such synthetic alternative can lead to better yields, but the need for two reaction steps, instead of a single one as described in WO2005/104745, is not the best solution for an industrial application. Additionally, WO2014/027045 discloses the use of a high temperature in the first step and the use of a highly corrosive and toxic reagent in the second step, namely thionyl chloride that produces environmentally unfriendly SOx by-products. Three major disadvantages when compared to the mild conditions described in WO2005/104745.
Alternatively, WO2016/071792 claims a one-step process for the preparation of compound of formula (II) which comprises the reaction of ethyl isonipecotate with halogenated-acetaldehyde in a mixture of methanol:acetic acid together with a reducing agent as follows:

Although leading to better yields (90%) in comparison to those described in WO2005/104745 and WO2014/027045, the synthesis requires the use of methanolic-aqueous acidic solutions, which can degrade the ester moiety to some extent, prior to the reaction with the reductive agents.
WO2011/029896 describes an alternative process to prepare umeclidinium bromide through the use of different intermediates as follows:
wherein P is a protecting group; R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl; and X and Y are leaving groups, provided that X and Y are different.
However, this process is more complex than the process disclosed in WO2005/104745 because it encompasses a longer synthetic route and includes extra protection-deprotection steps.
Unsolvated crystalline forms of umeclidinium bromide have been disclosed as polymorphs of the active pharmaceutical ingredient (WO2014/027045, U.S. Pat. No. 9,273,001 B2), showing that the compound may give rise to a variety of solids having distinct physical properties. The preparation of pure umeclidinium bromide in a single crystalline form has been a challenge for the industry as umeclidinium bromide is highly susceptible to forming solvates. Umeclidinium bromide solvates include a methanol solvate (CZ27764 (Sanofi)), and ethanol, 2-propanol, 2-methylpropan-1-ol, chlorobenzene and p-xylene solvates have been disclosed (WO2014/027045, U.S. Pat. No. 9,273,001 B2). 1-Propanol has been used as the solvent in the final process step to minimize solvate formation (U.S. Pat. No. 9,273,001 B2) avoiding the resuspension of the compound in ethyl acetate, methanol and water, which was previously required (example 84, Method B, WO2005/104745).
In order to fulfill the umeclidinium bromide market demand, there is a need to develop more efficient processes. Namely, processes that offer advantages over those previously disclosed in WO2016/071792, WO2005/104745, WO2014/027045 and WO2011/029896. There is also a need to provide processes that prepare umeclidinium bromide in a single, pure crystalline form with a consistent level of crystallinity and chemical purity.